Oral pulsed dose drug delivery system

ABSTRACT

A multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts, comprising an immediate-release component and an enteric delayed-release component wherein (1) the enteric release coating has a defined minimum thickness and/or (2) there is a protective layer between the pharmaceutically active amphetamine salt and the enteric release coating and/or (3) there is a protective layer over the enteric release coating. The product can be composed of either one or a number of beads in a dosage form, including either capsule, tablet, or sachet method for administering the beads.

[0001] This application is a Continuation of U.S. application Ser. No.09/807,462, which is a Continuation-in-part of application Ser. No.09/176,542, filed Oct. 21, 1998 now U.S. Pat. No. 6,322,819, thecontents of which are incorporated herein by reference.

[0002] This invention pertains to a multiple unit dosage form deliverysystem comprising one or more amphetamine salts for administering theamphetamine salts to a recipient.

BACKGROUND OF THE INVENTION

[0003] Traditionally, drug delivery systems have focused onconstant/sustained drug output with the objective of minimizing peaksand valleys of drug concentrations in the body to optimize drug efficacyand to reduce adverse effects. A reduced dosing frequency and improvedpatient compliance can also be expected for the controlled/sustainedrelease drug delivery systems, compared to immediate releasepreparations. However, for certain drugs, sustained release delivery isnot suitable and is affected by the following factors:

[0004] First pass metabolism: Some drugs, such as β blockers,β-estradiol, and salicylamide, undergo extensive first pass metabolismand require fast drug input to saturate metabolizing enzymes in order tominimize pre-systemic metabolism. Thus, a constant/sustained oral methodof delivery would result in reduced oral bioavailability.

[0005] Biological tolerance: Continuous release drug plasma profiles areoften accompanied by a decline in the pharmacotherapeutic effect of thedrug, e.g., biological tolerance of transdermal nitroglycerin.

[0006] Chronopharmacology and circadian rhythms: Circadian rhythms incertain physiological functions are well established. It has beenrecognized that many symptoms and onset of disease occur during specifictime periods of the 24 hour day, e.g., asthma and angina pectorisattacks are most frequently in the morning hours (1,2).

[0007] Local therapeutic need: For the treatment of local disorders suchas inflammatory bowel disease, the delivery of compounds to the site ofinflammation with no loss due to absorption in the small intestine ishighly desirable to achieve the therapeutic effect and to minimize sideeffects.

[0008] Gastric irritation or drug instability in gastric fluid: Forcompounds with gastric irritation or chemical instability in gastricfluid, the use of a sustained release preparation may exacerbate gastricirritation and chemical instability in gastric fluid.

[0009] Drug absorption differences in various gastrointestinal segments:In general, drug absorption is moderately slow in the stomach, rapid inthe small intestine, and sharply declining in the large intestine.Compensation for changing absorption characteristics in thegastrointestinal tract may be important for some drugs. For example, itis rational for a delivery system to pump out the drug much faster whenthe system reaches the distal segment of the intestine, to avoid theentombment of the drug in the feces.

[0010] Pulsed dose delivery systems, prepared as either single unit ormultiple unit formulations, and which are capable of releasing the drugafter a predetermined time, have been studied to address theaforementioned problematic areas for sustained release preparations.These same factors are also problematic in pulsed dose formulationdevelopment. For example, gastrointestinal transit times vary not onlyfrom patient to patient but also within patients as a result of foodintake, stress, and illness; thus a single-unit pulsed-release systemmay give higher variability compared to a multiple unit system.Additionally, drug layering or core making for multiple unit systems isa time-consuming and hard-to-optimize process. Particularly challengingfor formulation scientists has been overcoming two conflicting hurdlesfor pulsatile formulation development, i.e., lag time and rapid release.

[0011] Various enteric materials, e.g., cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,and the EUDRAGIT® acrylic polymers, have been used as gastroresistant,enterosoluble coatings for single drug pulse release in the intestine(3). The enteric materials, which are soluble at higher pH values, arefrequently used for colon-specific delivery systems. Due to theirpH-dependent attributes and the uncertainty of gastric retention time,in-vivo performance as well as inter- and intra-subject variability aremajor issues for using enteric coated systems as a time-controlledrelease of drugs.

[0012] A retarding swellable hydrophilic coating has been used for oraldelayed release systems (4,5). It was demonstrated that lag time waslinearly correlated with coating weight gain and drug release was pHindependent.

[0013] Hydroxypropyl methylcellulose barriers with erodible and/orgellable characteristics formed using press coating technology fortablet dosage forms have been described to achieve time-programmedrelease of drugs (6). Barrier formulation variables, such as grade ofhydroxypropyl methylcellulose, water-soluble and water-insolubleexcipients, significantly altered the lag time and the release rate fromthe center cores.

[0014] Special grades of hydroxypropyl methylcellulose, e.g., METOLOSE®60SH, 90SH (Shin-Etsu Ltd., Japan), and METHOCEL® F4M (Dow ChemicalCompany, USA), as a hydrophilic matrix material have been used toachieve bimodal drug release for several drugs, i.e., aspirin,ibuprofen, and adinazolam (7). Bimodal release is characterized by arapid initial release, followed by a period of constant release, andfinalized by a second rapid drug release.

[0015] Tablets or capsules coated with a hydrophobic wax-surfactantlayer, made from an aqueous dispersion of carnauba wax, beeswax,polyoxyethylene sorbitan monooleate, and hydroxypropyl methylcellulosehave been used for rapid drug release after a predetermined lag time.For example,. However, even though a two-hour lag time was achieved forthe model drug theophylline at a higher coating level (60%), three hourswere required for a complete release of theophylline after the lag time.(8)

[0016] A sustained-release drug delivery system is described in U.S.Pat. No. 4,871,549. When this system is placed into dissolution mediumor the gastrointestinal tract, water influx and the volume expansion ofthe swelling agent cause the explosion of the water permeable membrane.The drug thus releases after a predetermined time period.

[0017] The OROS® push-pull system (Alza Company) has been developed forpulsatile delivery of water-soluble and water-insoluble drugs (9, 10),e.g. the OROS-CT® system and is based on the swelling properties of anosmotic core compartment which provides a pH-independent,time-controlled drug release.

[0018] The PULSINCAP® dosage form releases its drug content at either apredetermined time or at a specific site (e.g., colon) in thegastrointestinal tract (11). The drug formulation is contained within awater-insoluble capsule body and is sealed with a hydrogel plug. Uponoral administration, the capsule cap dissolves in the gastric juice andthe hydrogel plug swells. At a controlled and predetermined time point,the swollen plug is ejected from the PULSINCAP® dosage form and theencapsulated drug is released. A pulsatile capsule system containingcaptopril with release after a nominal 5-hr period was found to performreproducibly in dissolution and gamma scintigraphy studies. However, inthe majority of subjects, no measurable amounts of the drug wereobserved in the blood, possibly due to instability of the drug in thedistal intestine. (12)

[0019] ADDERAL® comprises a mixture of four amphetamine salts which, incombination, is indicated for treatment of Attention DeficitHyperactivity Disorder in children from 3-10 years of age. Onedisadvantage of current treatment is that a tablet form is commonly usedwhich many young children have difficulty in swallowing. Anotherdisadvantage of current treatment is that two separate doses areadministered, one in the morning and one approximately 4-6 hours later,commonly away from home under other than parental supervision. Thiscurrent form of treatment, therefore, requires a second treatment whichis time-consuming, inconvenient and may be problematic for thosechildren having difficulties in swallowing tablet formulations.

SUMMARY OF THE INVENTION

[0020] Accordingly, in view of a need for successfully administering amultiple unit pulsed dose of amphetamine salts and mixtures thereof, thepresent invention provides an oral multiple unit pulsed dose deliverysystem for amphetamine salts and mixtures thereof. FIG. 1 illustratesthe desired target plasma level profile of the pharmaceutical activecontained within the delivery system.

[0021] In accordance with a preferred embodiment of the presentinvention, there is provided a pharmaceutical composition for deliveringone or more pharmaceutically active amphetamine salts that includes:

[0022] (a) one or more pharmaceutically active amphetamine salts thatare covered with an immediate release coating, and

[0023] (b) one or more pharmaceutically active amphetamine salts thatare covered with an enteric release coating wherein (1) the entericrelease coating has a defined minimum thickness and/or (2) there is aprotective layer between the at least one pharmaceutically activeamphetamine salt and the enteric release coating and/or (3) there is aprotective layer over the enteric release coating.

[0024] In one embodiment, the immediate release and enteric releaseportions of the composition are present on the same core.

[0025] In another embodiment, the immediate release and enteric releasecomponents are present on different cores.

[0026] It is also contemplated that the composition may include acombination of the hereinabove referred to cores (one or more cores thatinclude both components on the same core and one or more cores thatinclude only one of the two components on the core).

[0027] The present invention provides a composition in which there isimmediate release of drug and enteric release of drug wherein theenteric release is a pulsed release and wherein the drug includes one ormore amphetamine salts and mixtures thereof.

[0028] The immediate release component releases the pharmaceutical agentin a pulsed dose upon oral administration of the delivery system.

[0029] The enteric release coating layer retards or delays the releaseof the pharmaceutical active or drug for a specified time period (“lagtime”) until a predetermined time, at which time the release of the drugis rapid and complete, i.e., the entire dose is released within about30-60 minutes under predetermined environmental conditions, i.e. aparticular location within the gastrointestinal tract.

[0030] The delay or lag time will take into consideration factors suchas transit times, food effects, inflammatory bowel disease, use ofantacids or other medicaments which alter the pH of the GI tract.

[0031] In a preferred embodiment, the lag time period is onlytime-dependent, i.e., pH independent. The lag time is preferably within4 to 6 hours after oral administration of the delivery system.

[0032] In one aspect, the present invention is directed to a compositionthat provides for enteric release of at least one pharmaceuticallyactive amphetamine salt, including at least one pharmaceutically activeamphetamine salt that is coated with an enteric coating wherein (1) theenteric release coating has a defined minimum thickness and/or (2) thereis a protective layer between the at least one pharmaceutically activeamphetamine salt and the enteric release coating and/or (3) there is aprotective layer over the enteric release coating.

[0033] In attempting to provide for enteric release of an amphetaminesalt, applicants found that use of an enteric release coating asgenerally practiced in the art did not provide effective entericrelease.

[0034] Typical enteric coating levels did not meet the aboverequirements for the desired dosage profile of amphetamine salts. Usingthe typical amount of enteric coating (10-20μ) resulted in undesiredpremature leakage of the drug from the delivery system into the uppergastrointestinal tract and thus no drug delivery at the desired locationin the gastrointestinal tract after the appropriate lag time. Thus thiscoating did not meet the requirements for the drug release profile toprovide full beneficial therapeutic activity at the desired time.

[0035] Surprisingly, applicants found that using a thicker applicationof enteric coating on the formulation allowed for the second pulsed doseto be released only and completely at the appropriate time in thedesired predetermined area of the gastrointestinal tract, i.e., in theintestine.

[0036] This was surprising because an increase in thickness of about5-10μ of enteric coatings above a minimum thickness of about 10-20μtypically does not have a significant effect on release of drug fromwithin such coatings. Enteric coatings typically are pH dependent andwill only dissolve/disperse when exposed to the appropriate environment.Typically, application of a thicker coating (greater than 20μ) will onlymarginally increase the time for complete release at the appropriateenvironmental condition i.e., for a brief period of time (20 minutes).Using the typical coating, applicants could not achieve the desiredresult—rather, the coating leaked before the predetermined time in aninappropriate environment resulting in significant loss of thetherapeutic agent.

[0037] Accordingly, in one aspect, the pulsed enteric release of theamphetamine salts is accomplished by employing a certain minimumthickness of the enteric coating.

[0038] In one embodiment of the invention, the pulsed dose deliverycomprises a composition which comprises one or more pharmaceuticallyactive amphetamine salts; an enteric coating over the one or morepharmaceutically active amphetamine salts, wherein the thickness of theenteric coating layer is at least 25%; a further layer of one or morepharmaceutically active amphetamine salts over the enteric coatinglayer; and an immediate release layer coating. The thicker entericcoating surprisingly provides the required delayed immediate release ofthe pharmaceutically active amphetamine salt at the desired time in thedesired area of the gastrointestinal tract. FIG. 2 illustrates a modelof this delivery system.

[0039] In this aspect, the one or more pharmaceutically activeamphetamine salts can be provided within or as a part of a core seedaround which the enteric coating is applied. Alternatively, a core seedcan be coated with one or more layers of one or more pharmaceuticallyactive amphetamine salts.

[0040] It has further been discovered that a delayed immediate releasedrug delivery can also be accomplished by coating the drug first with aprotective layer prior to applying the enteric coating.

[0041] Thus, in another embodiment, the pulsed enteric release isaccomplished by employing a protective layer between the drug and theenteric coating. When using a protective coating, the enteric coatingmay be of an increased thickness or may be of lower thickness.

[0042] Thus, in another aspect, the object of the invention is met byproviding a composition comprising one or more pharmaceutically activeamphetamine salts; a protective layer coating over the one or morepharmaceutically active amphetamine salt layer(s), and an entericcoating layer over the protective coating layer; a furtherpharmaceutically active amphetamine salt layer and an immediate releaselayer coating. In a preferred embodiment of this aspect, the thicknessof the enteric coating is at least 25μ, and the protective layercomprises an immediate release coating.

[0043] With respect to this embodiment of the invention, the one or morepharmaceutically active amphetamine salts can be provided within or as apart of a core seed, during the core seed manufacturing process, aroundwhich the protective coating is applied. Alternatively, a core seed canbe coated with one or more layers of one or more pharmaceutically activeamphetamine salts.

[0044] In another embodiment, the pulsed enteric release is accomplishedby employing a protective layer over the enteric coating.

[0045] Accordingly, in this embodiment of the present invention, thereis provided a pulsed dose release drug delivery system comprising one ormore pharmaceutically active amphetamine salts; an enteric coating layerover the pharmaceutically active amphetamine salt layer(s); and aprotective layer over the enteric coating; a second pharmaceuticallyactive amphetamine salt layer; and an immediate release layer coating.

[0046] In one aspect of this embodiment, the protective layer iscomprised of one or more components, which includes an immediate releaselayer and a modifying layer. The modifying layer is preferably comprisedof a semi water-permeable polymer. Applicants have surprisingly foundthat a semi-permeable polymer coating used in combination with animmediate release layer coating provided a delayed pulsed release drugdelivery profile when layered over the enteric coating.

[0047] Thus, in this embodiment, the protective layer comprises asemi-permeable polymer and an immediate release coating layer. In apreferred embodiment, the modifying layer comprises a first layer of asemi-permeable polymer which is adjacent to the enteric coating layerand a second coating layer over the semi-permeable polymer coating layercomprising an immediate release polymer coating layer.

[0048] In one aspect of this embodiment, a semi-permeable polymer, whichmay comprise a low water-permeable pH-insensitive polymer, is layeredonto the outer surface of the enteric layer, in order to obtainprolonged delayed release time. This semi-permeable polymer coatingcontrols the erosion of the pH-sensitive enteric polymer in an alkalinepH environment in which a pH-sensitive polymer will dissolve rapidly.Another pH-sensitive layer may be applied onto the surface of a lowwater-permeability layer to further delay the release time.

[0049] In a still further aspect of the invention, in addition to aprotective layer, the composition comprises an acid which isincorporated into the pharmaceutical active layer or coated onto thesurface of the active layer to reduce the pH value of the environmentaround the enteric polymer layer. The acid layer may also be applied onthe outer layer of the pH-sensitive enteric polymer layer, followed by alayer of low water-permeability polymer. The release of the active thusmay be delayed and the dissolution rate may be increased in an alkalineenvironment.

[0050] In a further embodiment, the protective coating may be used bothover the drug and over the enteric coating.

[0051] With respect to this embodiment of the invention, the one or morepharmaceutically active amphetamine salts can be provided within or as apart of a core seed, during the core seed manufacturing process, aroundwhich the enteric coating is applied. Alternatively, a core seed can becoated with one or more layers of one or more pharmaceutically activeamphetamine salts.

[0052] The drug delivery system of the present invention as describedherein preferably comprises one or a number of beads or beadlets in adosage form, either capsule, tablet, sachet or other method of orallyadministering the beads.

BRIEF DESCRIPTION OF THE DRAWINGS

[0053] FIG. 1 illustrates a multiple pulse drug delivery system targetplasma profile of the drug delivery system of the present invention. Theprofile reflects an immediate-release component followed by adelayed-release component.

[0054] FIG. 2 schematically illustrates the delayed-release system ofthe present invention.

[0055] FIG. 2a graphically illustrates a pulsed dose delivery system.

[0056] FIGS. 2b and c graphically illustrate the drug release mechanismfrom the proposed delivery system.

[0057] FIG. 3 is a plot of the percent drug released versus time fromthe drug-loaded pellets described in Example 1 which exemplifies theimmediate release component of the present invention.

[0058] FIG. 4 is a plot of the percent drug released versus time fromthe coated pellets described in Example 2 which exemplifies theimmediate release component and the delayed release components of thepresent invention.

[0059] FIG. 5 is a plot of the percent drug released versus time fromthe coated pellets of Example 3 which exemplifies the immediate releasecomponent and the delayed release components of the present invention.

[0060] FIG. 6 illustrates the drug release profile of coated pelletsdescribed in Example 4 which exemplifies the immediate release componentand the delayed release components of the present invention.

[0061] FIG. 7 is a plot of a profile of plasma amphetamine concentrationafter administration of a composite capsule containing the immediaterelease pellets and delayed release pellets from Examples 1 and 2,respectively.

[0062] FIG. 8 is a plot of a profile of plasma amphetamine concentrationafter administration of a composite capsule containing the immediaterelease pellets and delayed release pellets from Examples 1 and 3,respectively.

DETAILED DESCRIPTION OF THE INVENTION

[0063] The present invention comprises a core or starting seed, eitherprepared or commercially available product. The cores or starting seedscan be sugar spheres; spheres made from microcrystalline cellulose andany suitable drug crystals.

[0064] The materials that can be employed in making drug-containingpellets are any of those commonly used in pharmaceutics and should beselected on the basis of compatibility with the active drug and thephysicochemical properties of the pellets. The additives except activedrugs are chosen below as examples:

[0065] Binders such as cellulose derivatives such as methylcellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinylacetate copolymer and the like.

[0066] Disintegration agents such as corn starch, pregelatinized starch,cross-linked carboxymethylcellulose (AC-DI-SOL®), sodium starchglycolate (EXPLOTAB®), cross-linked polyvinylpyrrolidone (PLASDONE XL®),and any disintegration agents used in tablet preparations.

[0067] Filling agents such as lactose, calcium carbonate, calciumphosphate, calcium sulfate, microcrystalline cellulose, dextran,starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodiumchloride, polyethylene glycol, and the like.

[0068] Surfactants such as sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, bile salts, glyceryl monostearate,PLURONIC® line (BASF), and the like.

[0069] Solubilizers such as citric acid, succinic acid, fumaric acid,malic acid, tartaric acid, maleic acid, glutaric acid sodium bicarbonateand sodium carbonate and the like.

[0070] Stabilizers such as any antioxidation agents, buffers, acids, andthe like, can also be utilized.

[0071] Methods of Manufacturing the Core Include

[0072] a. Extrusion-Spheronization—Drug(s) and other additives aregranulated by addition of a binder solution. The wet mass is passedthrough an extruder equipped with a certain size screen. The extrudatesare spheronized in a marumerizer. The resulting pellets are dried andsieved for further applications.

[0073] b. High-Shear Granulation—Drug(s) and other additives aredry-mixed and then the mixture is wetted by addition of a bindersolution in a high shear-granulator/mixer. The granules are kneadedafter wetting by the combined actions of mixing and milling. Theresulting granules or pellets are dried and sieved for furtherapplications.

[0074] c. Solution or Suspension Layering—A drug solution or dispersionwith or without a binder is sprayed onto starting seeds with a certainparticle size in a fluid bed processor or other suitable equipment. Thedrug thus is coated on the surface of the starting seeds. Thedrug-loaded pellets are dried for further applications.

[0075] For purposes of the present invention, the core particles have adiameter in the range of about 50-1500 microns; preferably 100-800microns.

[0076] These particles can then be coated in a fluidized bed apparatuswith an alternating sequence of coating layers.

[0077] The core may be coated directly with a layer or layers of atleast one pharmaceutically active amphetamine salts and/or thepharmaceutically active amphetamine salt may be incorporated into thecore material. Pharmaceutical active amphetamine salts contemplated tobe within the scope of the present invention include amphetamine base,all chemical and chiral derivatives and salts thereof; methylphenidate,all chemical and chiral derivatives and salts thereof;phenylpropanolamine and its salts; and all other compounds indicated forthe treatment of attention deficit hyperactivity disorder (ADHD).

[0078] A protective layer may be added on top of the pharmaceuticalactive containing layer and also may be provided between active layers.A separation or protective layer may be added onto the surface of theactive-loaded core, and then the enteric layer is coated thereupon.Another active layer may also be added to the enteric layer to deliveran initial dose.

[0079] A protective coating layer may be applied immediately outside thecore, either a drug-containing core or a drug-layered core, byconventional coating techniques such as pan coating or fluid bed coatingusing solutions of polymers in water or suitable organic solvents or byusing aqueous polymer dispersions. Suitable materials for the protectivelayer include cellulose derivatives such as hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose,polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer,ethyl cellulose aqueous dispersions (AQUACOAT®, SURELEASE®), EUDRAGIT®RL 30D, OPADRY® and the like. The suggested coating levels are from 1 to6%, preferably 2-4% (w/w).

[0080] The enteric coating layer is applied onto the cores with orwithout seal coating by conventional coating techniques, such as pancoating or fluid bed coating using solutions of polymers in water orsuitable organic solvents or by using aqueous polymer dispersions. Allcommercially available pH-sensitive polymers are included. Thepharmaceutical active is not released in the acidic stomach environmentof approximately below pH 4.5, but not limited to this value. Thepharmaceutical active should become available when the pH-sensitivelayer dissolves at the greater pH; after a certain delayed time; orafter the unit passes through the stomach. The preferred delay time isin the range of two to six hours.

[0081] Enteric polymers include cellulose acetate phthalate, Celluloseacetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinylacetate phthalate, carboxymethylethylcellulose, co-polymerizedmethacrylic acid/methacrylic acid methyl esters such as, for instance,materials known under the trade name EUDRAGIT® L12.5, L100, or EUDRAGIT®S12.5, S100 or similar compounds used to obtain enteric coatings.Aqueous colloidal polymer dispersions or re-dispersions can be alsoapplied, e.g. EUDRAGIT(T L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100,EUDRAGIT® preparation 4110D (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30(FMC); KOLLICOAT MAE® 30D and 30DP (BASF); EASTACRYL® 30D (EastmanChemical).

[0082] The enteric polymers used in this invention can be modified bymixing with other known coating products that are not pH sensitive.Examples of such coating products include the neutral methacrylic acidesters with a small portion of trimethylammonioethyl methacrylatechloride, sold currently under the trade names EUDRAGIT® RS andEUDRAGIT® RL; a neutral ester dispersion without any functional groups,sold under the trade names EUDRAGIT® NE30D; and other pH independentcoating products.

[0083] The modifying component of the protective layer used over theenteric coating can include a water penetration barrier layer(semipermeable polymer) which can be successively coated after theenteric coating to reduce the water penetration rate through the entericcoating layer and thus increase the lag time of the drug release.Sustained-release coatings commonly known to one skilled in the art canbe used for this purpose by conventional coating techniques such as pancoating or fluid bed coating using solutions of polymers in water orsuitable organic solvents or by using aqueous polymer dispersions. Forexample, the following materials can be used, but not limited to:Cellulose acetate, Cellulose acetate butyrate, Cellulose acetatepropionate, Ethyl cellulose, Fatty acids and their esters, Waxes, zein,and aqueous polymer dispersions such as EUDRAGIT® RS and RL 30D,EUDRAGIT® NE 30D, AQUACOAT®, SURELEASE®, cellulose acetate latex. Thecombination of above polymers and hydrophilic polymers such asHydroxyethyl cellulose, Hydroxypropyl cellulose (KLUCEL®, HerculesCorp.), Hydroxypropyl methylcellulose (METHOCEL®, Dow Chemical Corp.),Polyvinylpyrrolidone can also be used.

[0084] An overcoating layer can further optionally be applied to thecomposition of the present invention. OPADRY®, OPADRY II® (Colorcon) andcorresponding color and colorless grades from Colorcon can be used toprotect the pellets from being tacky and provide colors to the product.The suggested levels of protective or color coating are from 1 to 6%,preferably 2-3% (w/w).

[0085] Many ingredients can be incorporated into the overcoatingformula, for example to provide a quicker immediate release, such asplasticizers: acetyltriethyl citrate, triethyl citrate, acetyltributylcitrate, dibutylsebacate, triacetin, polyethylene glycols, propyleneglycol and the others; lubricants: talc, colloidal silica dioxide,magnesium stearate, calcium stearate, titanium dioxide, magnesiumsilicate, and the like.

[0086] The composition, preferably in beadlet form, can be incorporatedinto hard gelatin capsules, either with additional excipients, or alone.Typical excipients to be added to a capsule formulation include, but arenot limited to: fillers such as microcrystalline cellulose, soypolysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose,sucrose, sorbitol, or any other inert filler. In addition, there can beflow aids such as fumed silicon dioxide, silica gel, magnesium stearate,calcium stearate or any other material imparting flow to powders. Alubricant can further be added if necessary by using polyethyleneglycol, leucine, glyceryl behenate, magnesium stearate or calciumstearate.

[0087] The composition may also be incorporated into a tablet, inparticular by incorporation into a tablet matrix, which rapidlydisperses the particles after ingestion. In order to incorporate theseparticles into such a tablet, a filler/binder must be added to a tablethat can accept the particles, but will not allow their destructionduring the tableting process. Materials that are suitable for thispurpose include, but are not limited to, microcrystalline cellulose(AVICEL®), soy polysaccharide (EMCOSOY®), pre-gelatinized starches(STARCH®) 1500, NATIONAL® 1551), and polyethylene glycols (CARBOWAX®).The materials should be present in the range of 5-75% (w/w), with apreferred range of 25-50% (w/w).

[0088] In addition, disintegrants are added in order to disperse thebeads once the tablet is ingested. Suitable disintegrants include, butare not limited to: cross-linked sodium carboxymethyl cellulose(AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®, PRIMOJEL®), andcross-linked polyvinylpolypyrrolidone (Plasone-XL). These materialsshould be present in the rate of 3-15% (w/w), with a preferred range of5-10% (w/w).

[0089] Lubricants are also added to assure proper tableting, and thesecan include, but are not limited to: magnesium stearate, calciumstearate, stearic acid, polyethylene glycol, leucine, glyceryl behanate,and hydrogenated vegetable oil. These lubricants should be present inamounts from 0. 1-10% (w/w), with a preferred range of 0.3-3.0% (w/w).

[0090] Tablets are formed, for example, as follows. The particles areintroduced into a blender along with AVICEL®, disintegrants andlubricant, mixed for a set number of minutes to provide a homogeneousblend which is then put in the hopper of a tablet press with whichtablets are compressed. The compression force used is adequate to form atablet; however, not sufficient to fracture the beads or coatings.

[0091] It will be appreciated that the multiple dosage form of thepresent invention can deliver rapid and complete dosages ofpharmaceutically active amphetamine salts to achieve the desired levelsof the drug in a recipient over the course of about 8 hours with asingle oral administration.

[0092] In so doing, the levels of drug in blood plasma of thepharmaceutically active amphetamine salts will reach a peak fairlyrapidly after about 2 hours, and after about 4 hours a second pulse doseis released, wherein a second fairly rapid additive increase of plasmadrug levels occurs which slowly decreases over the course of the next 12hours.

[0093] The following examples are presented to illustrate and do notlimit the invention.

EXAMPLES Example 1 Immediate Release Formulation

[0094] The following formulation was used to layer the drug onto sugarspheres. Nonpareil seeds (30/35 mesh, Paulaur Corp., NJ), 6.8 kg wereput into a FLM-15 fluid bed processor with a 9″ Wurster column andfluidized at 60° C. The suspension of mixed amphetamine salts (MAS) with1% HPMC E5 Premium (Dow Chemical) as a binder was sprayed onto the seedunder suitable conditions. Almost no agglomeration and no fines wereobserved with a yield of at least 98%. The drug-loaded cores were usedto test enteric coatings and sustained release coatings. TABLE 1Ingredients Amount (%) Nonpareil seed 88.00 mixed amphetamine salts11.40 METHOCEL ® E5 Premium 0.60 Water *

[0095] The drug release profile of the drug-loaded pellets of thisexample is shown in FIG. 3.

Example 2

[0096] The following formulation was used to coat the mixed amphetaminesalts loaded (MASL) pellets from Example 1 with the EUDRAGIT® L 30D-55(Rohm Pharma, Germany) coating dispersion. 2 kg of MASL pellets wereloaded into a fluid bed processor with a reduced Wurster column equippedwith a precision coater (MP 2/3, Niro Inc.). The coating dispersion wasprepared by dispersing Triethyl citrate, Talc and EUDRAGIT® L 30D-55into water and mixing for at least 30 minutes. Under suitablefluidization conditions, the coating dispersion was sprayed onto thefluidized MASL pellets. The spraying was continued until the targetedcoating level was achieved (20μ). The coated pellets were dried at30-35° C. for 5 minutes before stopping the process. The enteric coatedPPA pellets were tested at different pH buffers by a USP paddle method.The drug content was analyzed using HPLC. The results showed that theenteric coating delayed the drug release from the coated pellets untilafter exposure to pH 6 or higher (see Table 2 below). (Reference#AR98125-4) TABLE 2 Ingredients Amount (%) MASL pellets 40.00 EUDRAGIT ®L 30D-55 24.88 Triethyl citrate 2.52 Talc 2.60 Water *

[0097] The drug release profile of the coated pellets of this example isshown in FIG. 4.

Example 3

[0098] The following formulation was used to coat the MASL pellets fromExample 1 with the EUDRAGIT® 4110D (Rohm Pharma, Germany) coatingdispersion. MASL pellets (2 kg) were loaded in a fluid bed processorwith a reduced Wurster column (GPGC-15, Glatt). The coating dispersionwas prepared by dispersing Triethyl citrate, Talc and EUDRAGIT® 4110Dinto water and mixing for at least 30 minutes. Under suitablefluidization conditions, the coating dispersion was sprayed onto thefluidized MASL pellets. The spraying was continued until the targetedcoating level was achieved. The coated pellets were dried at 30-35° C.for 5 minutes before stopping the process. The enteric coated MASLpellets were tested using a USP paddle method at different pH buffers.The drug content was analyzed using HPLC. The enteric coating delayedthe drug release for several hours from the coated pellets until the pHvalue reached 6.8 or higher, as shown below in Table 3. (Reference#AR98125-3) TABLE 3 Ingredients Amount % MASL pellets 70.00 Eudragit ®4110D 26.24 Triethyl citrate  0.76 Talc  3.00 Water *

[0099] The drug release profile of coated pellets of this example isshown in FIG. 5.

Example 4

[0100] The following formulation was selected to coat the enteric coatedMASL pellets. Coated MASL pellets from Example 2 or coated MASL pelletsfrom Example 3 (2 kg of either) were loaded into a fluid bed processorwith a reduced Wurster column (GPGC-15, Glatt). The coating dispersionwas prepared by mixing SURELEASE® (Colorcon) and water for at least 15minutes prior to spraying. Under suitable fluidization conditions, thecoating dispersion was sprayed onto the fluidized pellets. The sprayingwas continued until the targeted coating level was achieved. The coatedpellets were coated with a thin layer of OPADRY® white (Colorcon) (2%)to prevent the tackiness of the coated pellets during storage. Thecoated pellets were then dried at 35-40° C. for 10 minutes beforedischarging from the bed. The drug dissolution from both coated pelletswas performed using a USP paddle method at different pH buffers. Thedrug content was analyzed using HPLC. The 8% SURELEASE® coating slightlysustained the drug release from EUDRAGIT® L 30D-55 coated pellets at pH7.5 buffer, while the SURELEASE® coating delayed the drug release up to2 hours after the buffer switched from pH 1 to pH 7.5. (Reference##AR98125-1) TABLE 4 Ingredients Amount, (%) Enteric coated MASL pellets90.00 SURELEASE ® 8.00 OPADRY ® white 2.00 Water *

[0101] The drug release profile of the coated pellets from this exampleis shown in FIG. 6.

Example 5

[0102] A pulsatile delivery system can be achieved by combining theimmediate release pellets (Example 1) with delayed release pellets(Example 2 or Example 3). The immediate-release pellets equivalent tohalf the dose and the delayed-release pellets equivalent to half thedose are filled into a hard gelatin capsule to produce the oral pulseddose delivery system. The delayed-release portion releases theamphetamine salts rapidly and completely, after a specified lag time.The capsule products containing immediate-release pellets anddelayed-release pellets (Example 1 plus Example 2 and Example 1 plusExample 3) were tested in a crossover human study. FIGS. 7 and 8 showthe typical profiles of plasma amphetamine concentration afteradministration of a composite capsule containing the immediate-releasepellets and delayed-release pellets from Examples 1 and 2 (10 mg doseeach pellet type) and a capsule containing the pellets fromimmediate-release pellets and delayed-release pellets from Examples 1and 3 (10 mg dose each pellet type), respectively. The general plasmaprofiles are similar to the desired target plasma level profile shown inFIG. 1.

[0103] It is to be understood, however, that the scope of the presentinvention is not to be limited to the specific embodiments describedabove. The invention may be practiced other than as particularlydescribed and still be within the scope of the accompanying claims.

CITED LITERATURE

[0104] 1. B. Lemmer, “Circadian Rhythms and Drug Delivery”, J.Controlled Release, 16, 63-74 (1991)

[0105] 2. B. Lemmer, “Why are so many Biological Systems Periodic?” inPulsatile Drug Delivery: Current Applications and Future Trends, RGurny, H E Junginger and N A Peppas, eds. (WissenschaftlicheVerlagsgesellschaft mbH Stuttgart, Germany 1993) pp.11-24

[0106] 3. X. Xu and P I Lee, “Programmable Drug Delivery from anErodible Association Polymer System”, Pharm. Res. 10(8), 1144-1152(1993)

[0107] 4. A. Gazzaniga, M E Sangalli, and F Giodano, “Oral ChonotropicDrug Delivery Systems: Achievement of Time and/or Site Specificity”, EurJ. Pharm. Biopharm., 40(4), 246-250 (1994)

[0108] 5. A Gazzaniga, C Busetti, L Moro, M E Sangalli and F Giordano,“Time Dependent Oral Delivery Systems for Colon Targeting”, S.T.P.Pharma Sciences 5(1), 83-88 (1996)

[0109] 6. U Conte, L Maggi, M L Torre, P Giunchedi and A Lamanna,“Press-coated Tablets for Time programmed Release of Drugs”,Biomaterials, 14(13), 1017-1023 (1993)

[0110] 7. A C Shah International Patent Application WO87/00044

[0111] 8. P S Walia, P Jo Mayer Stout and R Turton, “PreliminaryEvaluation of an Aqueous Wax Emulsion for Controlled Release Coating”,Pharm Dev Tech, 3(1), 103-113 (1998)

[0112] 9. F Theeuwes, “OROS® Osmotic System Development”, Drug Dev IndPharm 9(7), 1331-1357 (1983)

[0113] 10. F Theeuwes, “Triggered, Pulsed and Programmed Drug Delivery”in Novel Drug Delivery and its Therapeutic Application, L F Prescott andWS Nimmos. eds. (Wiley, New York, 1989) pp. 323-340

[0114] 11. M McNeil, A Rashid and H Stevens, “International Patent AppWO90/09168

[0115] 12. I R Wilding, S S Davis, M Bakhshaee, H N E Stevens, R ASparrow and J Brennan, “Gastrointestinal Transit and Systemic Absorptionof Captopril from a Pulsed Release Formulation”, Pharm Res 9(5), 654-657(1992)

1. A pharmaceutical composition for enteric delivery of one or morepharmaceutically active amphetamine salts comprising: (a) one or morepharmaceutically active amphetamine salts covered with an immediaterelease coating; and (b) one or more pharmaceutically active amphetaminesalts that are covered with an enteric release coating that provides forpulsed enteric release wherein the enteric release coating has athickness of at least 25μ.
 2. The pharmaceutical composition of claim 1wherein the one or more pharmaceutically active amphetamine salts arecoated onto a core.
 3. The pharmaceutical composition of claim 1 whereinthe one or more pharmaceutically active amphetamine salts areincorporated into a core.
 4. The pharmaceutical composition of claim 1,wherein the immediate release and enteric release portions of thecomposition are present on a single core.
 5. The pharmaceuticalcomposition of claim 1, wherein the immediate release and entericrelease components are present on different cores.
 6. A pharmaceuticalcomposition for enteric delivery of one or more pharmaceutically activeamphetamine salts comprising: (a) one or more pharmaceutically activeamphetamine salts covered with an immediate release coating; (b) one ormore pharmaceutically active amphetamine salts that are covered with anenteric release coating that provides for pulsed enteric release; and(c) a protective layer between the at least one pharmaceutically activeamphetamine salt and the enteric release coating.
 7. The pharmaceuticalcomposition of claim 6 wherein the one or more pharmaceutically activeamphetamine salts are coated onto a core.
 8. The pharmaceuticalcomposition of claim 6 wherein the one or more pharmaceutically activeamphetamine salts are incorporated into a core.
 9. The pharmaceuticalcomposition of claim 6 wherein the enteric release coating has a minimumthickness of 25μ.
 10. A pharmaceutical composition for delivering one ormore pharmaceutically active amphetamine salts comprising: (a) one ormore pharmaceutically active amphetamine salts covered with an immediaterelease coating; (b) one or more pharmaceutically active amphetaminesalts that are covered with an enteric release coating that provides forpulsed enteric release; and (c) a protective layer over the entericrelease coating.
 11. The pharmaceutical composition of claim 10 whereinthe one or more pharmaceutically active amphetamine salts are coatedonto a core.
 12. The pharmaceutical composition of claim 10 wherein theone or more pharmaceutically active amphetamine salts are incorporatedinto a core.
 13. The pharmaceutical composition of claim 10, wherein theimmediate release and enteric release portions of the composition arepresent on a single core.
 14. The pharmaceutical composition of claim10, wherein the immediate release and enteric release components arepresent on different cores.
 15. A pharmaceutical composition fordelivery of at least one amphetamine salt, comprising: (a) at least onepharmaceutically active amphetamine salt covered with an immediaterelease coating; and (b) at least one pharmaceutically activeamphetamine salt covered with an enteric release coating, said component(a) providing for an immediate release of amphetamine salt to provide afirst blood level of amphetamine salt and component (b) providing adelayed pulsed-release of amphetamine salt that increases the bloodlevel of amphetamine salt to a second level that is greater than thefirst level provided by component (a).
 16. The pharmaceuticalcomposition of claim 15 wherein the enteric release coating has aminimum thickness of 25 microns.
 17. The pharmaceutical composition ofclaim 15 wherein the delayed pulsed-release is from 4 to 6 hours afteradministration of the pharmaceutical composition.
 18. The pharmaceuticalcomposition of claim 15 wherein the delayed pulsed-release, releases theamphetamine salt in about 30 to 60 minutes after initiation of therelease.